This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- ES-101*: Effects of Environmental Exposures on Phenotypic Outcomes Using Non-Human Models. Farmers as a group have the highest occupational risk for prostate cancer, but the causes for this are unknown. The Agricultural Health Study associated exposure to certain organophosphorothioate pesticides with increased prostate cancer risk in farmers and professional pesticide applicators with a first-degree family history of prostate cancer. These findings indicate that exposure to these environmental contaminants may interact with a genetic predisposition toward prostate cancer, but the biologic mechanism(s) by which this might occur remain unclear. This information is critical not only for better defining the risks posed by these pesticides for farm workers and others exposed to these chemicals, but also may advance our understanding of prostate cancer progression in the general population. Experimental exploration of the mechanistic links between pesticide exposure and prostate cancer progression will be difficult in humans. Therefore, the objective of this proposal is to test the hypothesis that exposure to organophosphorothioates accelerates prostate cancer progression in a mouse model genetically predisposed to develop premalignant prostate lesions (B6:PTEN/luc) in order to establish an experimental platform for exploring these links. Our model employs sophisticated imaging technology which can be used to rapidly assess the effects of exposures to environmental challenges on prostate cancer progression. This model is generally applicable to evaluating other environmental exposures and can be used in ways not possible in humans to understand the mechanistic links between environmental exposures and the etiology of prostate cancer. PUBLIC HEALTH RELEVANCE: Epidemiologic studies indicate that farmers and others occupationally exposed to certain organophosphorothioate pesticides may have further increased risk for prostate cancer when there is a first degree family history of this disease. Because the mechanistic basis of this finding will be difficult to determine in humans, here we will explore whether exposure of mice genetically predisposed to develop prostate cancer to these pesticides affects disease progression. Elucidating the mechanisms by which certain pesticides influence prostate cancer progression may impact the prevention, detection, and treatment of this disease.